Non-inferiority Trial Research Articles

Abstract GS02-06: Recurrence-free survival following sentinel node-positive breast cancer without completion axillary lymph node dissection – first results from the international randomized SENOMAC trial

Abstract Background The omission of a completion axillary lymph node dissection (cALND) after a positive sentinel lymph node (SLN) biopsy in patients with clinically node-negative breast cancer has been demonstrated to yield survival outcomes non-inferior to routine cALND in breast-conserving surgery followed by whole-breast irradiation (ACOSOG Z0011 and IBCSG 23-01 trials), and to axillary radiotherapy (RT) regardless of breast surgery (EORTC AMAROS trial). Mainly due to the under-representation of mastectomy patients, and a limited number of observed events compromising statistical power, the international randomized SENOMAC trial was initiated in 2015. The main aim of this non-inferiority trial was to address knowledge gaps relating to individuals treated by mastectomy, those with larger tumors and those with SLN extracapsular extension. Method The SENOMAC trial (NCT 02240472) enrolled patients with cT1-3cN0 primary breast cancer and 1-2 SLN macrometastases at 67 sites in five countries between January 27, 2015, and December 31, 2021. Participants were randomized 1:1 between cALND (standard) and omission of cALND (intervention). Stratification was per country. Breast-conserving surgery and mastectomy were eligible surgical interventions. Preoperative axillary ultrasound was mandatory; patients with non-palpable suspicious axillary lymph nodes, even if proven metastatic by biopsy, were eligible. SLN extracapsular extension was allowed. Adjuvant radiotherapy was dictated by national guidelines and not by the trial protocol. Statistical sample size calculation was based on the primary outcome overall survival. Non-inferiority was defined as a 5-year overall survival not worsened by more than 2.5% when refraining from cALND after the observation of 190 all-cause deaths in a target sample size of 3000 included patients. In the present analysis, the pre-specified secondary outcome of recurrence-free survival is reported. Results Out of 2766 randomized individuals, 2539 comprised the per-protocol population: 1204 in the standard and 1335 in the intervention group. Median follow-up was 37.1 months (1.5-75.0) and median age at inclusion 61 years (range 20-94). Most tumors belonged to the luminal subtype (93.6%); tumor stage was T1 in 1358 (53.5%), T2 in 1034 (40.7%) and T3 in 146 participants (5.8%). Out of 347 participants with suspicious lymph nodes on ultrasound, 36 had confirmed non-palpable metastasis. SLN extracapsular extension was reported in 866 (34.1%). The breast was conserved in 1621 (63.8%) and a mastectomy performed in 918 (36.2%) patients. Most patients (2127, 83.8%) received radiotherapy including nodal target volumes. In 34.1% of the standard group, additional non-SLN metastases were identified on cALND. Overall, 104 recurrences were reported, 54 (4.5%) in the standard and 50 (3.7%) in the intervention group. Of these, 11 recurrences were found in the ipsilateral axilla: 5 (0.4%) and 6 (0.5%), respectively. Recurrence-free survival did not differ between groups (country-adjusted HR 0.89, 95% CI 0.65-1.20). Conclusion Despite extended inclusion criteria, there was no difference in recurrence-free survival whether cALND was omitted (intervention) or not (standard). Patients undergoing mastectomy will specifically be addressed in subgroup analyses. Long-term follow-up is crucial considering the high proportion of luminal cancers. Citation Format: Jana de Boniface, Tove Tvedskov, Bergkvist Leif, Jan Frisell, Yvette Andersson, Sara Alkner, Malin Sund, Roger Olofsson Bagge, Dan Lundstedt, Oreste Davide Gentilini, Michalis Kontos, Toralf Reimer, Birgitte Offersen, Thorsten Kühn, Lisa Rydén, Peer Christiansen. Recurrence-free survival following sentinel node-positive breast cancer without completion axillary lymph node dissection – first results from the international randomized SENOMAC trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS02-06.

Abstract GS03-02: Mammographic surveillance in early breast cancer patients aged 50 years or over: results of the Mammo-50 non-inferiority trial of annual versus less frequent mammography

Abstract Introduction: Annual surveillance mammograms for an unspecified period, after treatment for early breast cancer, are widely practised in USA and Europe and represent a significant healthcare cost. Current UK guidelines recommend annual mammograms up to 5 years, then reverts to 3 year screening without specified risk stratification. Further evidence is needed to determine the optimum frequency and duration of mammographic surveillance. Methods: A multi-centre, randomised controlled, phase III trial of annual mammography versus 2-yearly for conservation surgery and 3-yearly mammograms for mastectomy patients up to 9 years. Women were eligible if aged 50 years or over at initial diagnosis of breast cancer (invasive or DCIS), and recurrence free 3 years post curative surgery. Primary outcome was breast cancer specific survival (BCSS). Secondary outcomes include recurrence free interval (RFI) and overall survival (OS). BCSS event was defined as deaths from breast cancer and RFI as any locoregional or distant invasive recurrence or new breast primary. 5000 women were needed to detect a 3% absolute non-inferiority (NI) margin for BCSS with 2.5% one-sided alpha and at least 85% power. Analyses were carried out on intention-to-treat basis. Results: 5235 women were randomised between April 2014 and September 2018. 4347 (83%) women were aged 55-75 years, 4203 (80%) had undergone conservation surgery, 4564 (87%) had invasive disease, 1162 (22%) had node positive disease, 4330 (83%) had ER positive tumours and 3812 (73%) were taking hormone therapy at the time of randomisation. Patient characteristics were balanced across arms. With a median of 5.4 years follow-up (interquartile range 4.6-5.9), 319 women have died; 104 of breast cancer (53 on annual arm; 51 on less frequent arm). BCSS at 5 years was 98.2% (95% CI 97.5-98.6%) on annual arm and 98.3% (95% CI 97.7-98.8%) on less frequent arm. Hazard ratio (HR) was 1.04 (95% CI 0.71 -1.54), demonstrating non-inferiority of less frequent mammograms at the 3% margin (NI p< 0.0001; critical value 2.71) and the 1% margin (NI p=0.02; critical value 1.56). 320 (6%) women had a new invasive breast cancer event (55 loco-regional recurrences, 85 new breast primaries, 139 distant recurrences and 41 with multiple invasive events); 164 on the annual arm compared to 156 on the less frequent arm. Five-year RFI was 94.2% (95% CI 93.2-95.1%) for the annual arm and 94.4% (95% CI 93.4-95.3%) for the less frequent arm; HR= 1.03; (95% CI 0.83-1.28) demonstrating non-inferiority at a 2% margin (NI p=0.006; critical value 1.36). OS at 5 years was 94.9% (95% CI 93.9-95.7%) on the annual arm and 94.3% (95% CI 93.3-95.2%) on the less frequent arm. Hazard ratio (HR) was 1.18 (95% CI 0.94 -1.47), demonstrating non-inferiority of less frequent mammograms at the 3% margin (NI p=0.003; critical value 1.61) and the 2.5% margin (NI p=0.02; critical value 1.51). A total of 14987 mammograms have been performed on the annual arm and 8047 on the less frequent arm. 1967 (75%) of 2618 women on the annual arm complied with their allocated schedule compared to 1775 (68%) of 2617 women on the less frequent arm. COVID-19 pandemic affected compliance; it is estimated that 345 (7%) women missed mammograms during the pandemic. A sensitivity analysis was performed on the 72% of women who fully complied with their scheduled mammograms as per protocol, and again NI was demonstrated for BCSS, RFI and OS. Conclusions: For patients aged 50 or older and 3 years post diagnosis, Mammo-50 demonstrated that less frequent mammograms were no worse than annual mammograms. These results provide evidence for less frequent mammographic surveillance for this patient population. Citation Format: Janet Dunn, Peter Donnelly, Nada Elbeltagi, Andrea Marshall, Alastair Thompson, Riccardo Audisio, Sarah Pinder, David Cameron, Amy Campbell, Sue Hartup, Lesley Turner, Annie Young, Helen Higgins, Eila Watson, Sophie Gasson, Peter Barrett-Lee, Claire Hulme, Bethany Shinkins, Peter Hall, Andy Evans. Mammographic surveillance in early breast cancer patients aged 50 years or over: results of the Mammo-50 non-inferiority trial of annual versus less frequent mammography [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS03-02.

Abstract PO1-19-03: The T-REX trial: a randomized international non-inferiority trial on Tailored Regional EXternal beam radiotherapy in clinically node-negative breast cancer patients with 1-2 sentinel node macrometastases

Abstract Background: Modern systemic treatment has reduced the incidence of regional recurrences and improved survival in breast cancer (BC). It is thus questionable whether regional radiotherapy (RT) is still indicated in patients with sentinel lymph node (SLN) macrometastases. Postoperative regional RT is associated with an increased risk of arm morbidity, pneumonitis, cardiac disease, and secondary cancer. Therefore, there is a need to individualize the indication for regional RT in relation to risk of recurrence. Trial design: In this multicenter, prospective randomized phase 3 trial, eligible patients have a clinically node-negative, estrogen receptor-positive, HER2-negative BC with 1-2 SLN macrometastases, and have not undergone completion axillary lymph node dissection. Participants are randomly assigned to receive regional RT (standard arm) or not (intervention arm). Regional RT includes the axillary levels I-III and the supraclavicular fossa. Internal mammary nodes are targeted in selected patients. After breast-conserving surgery (BCS), RT to the remaining breast is given in both groups while after mastectomy, chest-wall RT is only given in the standard arm. In the intervention arm, chest wall RT may be indicated in selected cases with extensive multifocality, according to national guidelines. RT quality assurance is an integral part of the trial. In addition, material from the primary tumor, SLN metastases and any recurrences is subjected to gene expression analysis to identify both prognostic markers for locoregional recurrence and predictive markers for the benefit of regional RT. After confirmation of eligibility and written informed consent, patients are randomized 1:1 between the treatment arms. Allocation is stratified by trial site and breast surgery (BCS vs. mastectomy). Participation in T-REX should not affect decisions on systemic adjuvant treatment. Eligibility criteria: Trial inclusion and exclusion criteria are given in Table 1. Specific aims: The main aim of the trial is to investigate if the omission of regional RT is non-inferior to routine regional RT in clinically node-negative BC patients with estrogen receptor-positive, HER2-negative T1-2 tumors with 1-2 SLN macrometastases not receiving axillary lymph node dissection. Secondary aims are to investigate whether refraining from regional RT reduces arm morbidity and late RT side effects, and improves short- and long-term health-related quality of life. In addition, the use of genomic classifiers for the prognostication of locoregional recurrences and the prediction of a benefit from regional RT will be investigated. Statistical methods: Primary outcome is recurrence free survival (RFS) at five years. Non-inferiority will be declared if the outcome in the intervention arm is not more than 4.5 percentage units below the standard arm, corresponding to a hazard ratio of 1.41 assuming 88% 5-year RFS with standard treatment. Secondary outcomes include locoregional recurrence, overall survival, patient-reported arm morbidity, and health-related quality of life. Accrual: The trial will include 1350 patients in Sweden, Norway and Finland from April 2023 to December 2028. First sites have been opened in April 2023. Contact information: Primary Investigator: Sara Alkner, Skåne University Hospital, Lund University, sara.alkner@med.lu.se. Responsible for the biobank: Per Karlsson, Sahlgrenska University Hospital, Gothenburg University, per.karlsson@oncology.gu.se. Inclusion and exclusion criteria Citation Format: Sara Alkner, Jana de Boniface, Dan Lundstedt, Ingvil Mjaaland, Lisa Rydén, Johan vikström, Pär-Ola Bendahl, Erik Holmberg, Helena Sackey, Elinore Wieslander, Per Karlsson. The T-REX trial: a randomized international non-inferiority trial on Tailored Regional EXternal beam radiotherapy in clinically node-negative breast cancer patients with 1-2 sentinel node macrometastases [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-03.

Study on the comparison between Bosentan and Macitentan in the treatment of persistent pulmonary hypertension of the newborns, simultaneously on sildenafil: A randomized double-blinded non-inferiority parallel clinical trial

BackgroundPersistent Pulmonary Hypertension of the newborn (PPHN) is characterized by sustained elevated Pulmonary Artery Pressure (PAP). Drug resistance and the adverse effects of current therapeutic agents warrant investigation of other targeted therapies. Bosentan has shown benefits in affected neonates. However, trials reported the association with unwanted effects. Thus, in this study, we assess another agent in the same family, Macitentan. However, its efficacy in the treatment of PPHN is not yet reported. Hence, this study evaluated the effect of Macitentan compared to Bosentan in terms of efficacy and safety in the treatment of PPHN. MethodsThis randomized, double-blinded non-inferiority clinical trial was conducted in Shahid Akbar Abadi hospital, Tehran, Iran. Sixty clinically stable neonates with signs suggestive of PPHN were randomly allocated into two groups (n = 30 in each group) and they received either Bosentan 1 mg/kg/dose BD (twice daily) or Macitentan 1 mg/kg/dose BD simultaneously with sildenafil. The echocardiographic and laboratory indices of efficacy and safety were compared between groups. SPAP (systolic pulmonary artery pressure) was used to assess the non-inferiority of the Macitentan compared to the Bosentan in their respective doses used in the study. ResultsParticipants’ mean (SD) age was 3.53 (1.21) days, and 55% were female. No mortality case occurred. SPAP was reduced in both Bosentan and Macitenan groups with the mean difference in SPAP of 9 (95% CI: 7.34–10.65) in Bosentan and SPAP mean difference of 14 (95% CI: 12.12–15.86) in Macitentan group. Categorical comparison of primary outcome improvement showed that Macitentan was superior to Bosentan with a 10% non-inferiority margin. Similar results were obtained in other echocardiographic indices. Also, no significant alterations were observed in laboratory safety parameters. ConclusionMacitentan 1 mg/kg/dose BD (twice daily) is non-inferior to Bosentan 1 mg/kg/dose BD in improving echo outcomes of PPHN and it was even more effective in improving some of these. Also, it is non-inferior to Bosentan in terms of safety. Trial registry number(IRCT20160120026115N9).

Intramuscular versus enteral penicillin prophylaxis to prevent progression of rheumatic heart disease: Study protocol for a noninferiority randomized trial (the GOALIE trial)

Rheumatic Heart Disease (RHD) persists as a major cardiovascular driver of mortality and morbidity among young people in low-and middle-income countries. Secondary antibiotic prophylaxis (SAP) with penicillin remains the cornerstone of RHD control, however, suboptimal treatment adherence undermines most secondary prevention programs. Many of the barriers to optimal SAP adherence are specific to the intramuscular form of penicillin and may potentially be overcome by use of oral penicillin. This noninferiority trial is comparing the efficacy of intramuscular to oral penicillin SAP to prevent progression of mild RHD at 2 years. The Intramuscular vs Enteral Penicillin Prophylaxis to Prevent Progression of Rheumatic Heart Disease (GOALIE) trial is randomizing Ugandan children aged 5 to 17 years identified by echocardiographic screening with mild RHD (Stage A or B as defined by 2023 World Heart Federation criteria) to Benzathine Benzyl Penicillin G (BPG arm, every-28-day intramuscular penicillin) or Phenoxymethyl Penicillin (Pen V arm, twice daily oral penicillin) for a period of 2 years. A blinded echocardiography adjudication panel of 3 RHD experts and 2 cardiologists is determining the echocardiographic stage of RHD at enrollment and will do the same at study completion by consensus review. Treatment adherence and study retention are supported through peer support groups and case management strategies. The primary outcome is the proportion of children in the Pen V arm who progress to more advanced RHD compared to those in the BPG arm. Secondary outcomes are patient-reported outcomes (treatment acceptance, satisfaction, and health related quality of life), costs, and cost-effectiveness of oral compared to intramuscular penicillin prophylaxis for RHD. A total sample size of 1,004 participants will provide 90% power to demonstrate noninferiority using a margin of 4% with allowance for 7% loss to follow-up. Participant enrollment commenced in October 2023 and final participant follow-up is expected in December 2026. The graphical abstract (Fig. 1) summarizes the flow of echocardiographic screening, participant enrollment and follow-up. The GOALIE trial is critical in global efforts to refine a pragmatic approach to secondary prevention for RHD control. GOALIE insists that the inferiority of oral penicillin be proven contemporarily and against the most important near-term clinical outcome of progression of RHD severity. This work also considers other factors that could influence the adoption of oral prophylaxis and change the calculus for acceptable efficacy including patient-reported outcomes and costs. ClinicalTrials.gov: NCT05693545.

SINGLE-PILL COMBINATION OF THIRD-DOSE TRIPLE ANTIHYPERTENSIVE THERAPY VERSUS STANDARD-DOSE MONOTHERAPY IN PATIENTS WITH MILD TO MODERATE HYPERTENSION

Objective: The study compared the single-pill combination of third-dose triple antihypertensive therapy (amlodipine 1.67 mg, losartan potassium 16.67 mg, chlorthalidone 4.17 mg) with standard-dose monotherapy (amlodipine 5mg) in reducing systolic blood pressure (SBP) among patients with mild to moderate hypertension. Design and method: This was a multicenter, randomized, double-blind, active-controlled, parallel-group phase III noninferiority trial. Eligible participants aged >=19 years with SBP >=140 to <180 mmHg and diastolic blood pressure (DBP) <110 mmHg after 4 weeks placebo run-in period were randomized to either 8 weeks of combination therapy (ALC) or monotherapy (A5). The primary efficacy endpoint, noninferiority in SBP reduction, was assessed using the upper limit of the one-sided 97.5% confidence interval (97.5%CI) for the difference in SBP reduction between treatments at week 8, with a noninferiority margin of 3 mmHg. Results: The efficacy endpoint analysis included 167 and 166 in the ALC and A5 groups. After 8 weeks, the ALC and A5 groups showed SBP reductions of -18.3±11.9 and -19.4±12.5, respectively, and DBP reductions of -8.5±7.3 and -9.8±7.0 mmHg, respectively (p>0.025 for both). The unadjusted least-square mean (LSM) difference in SBP reduction was 1.15 mmHg, with a 97.5%CI upper limit of 3.51 mmHg. More female patients were allocated to the A5 than the ALC groups (47.6% vs. 34.1%, p=0.012). Both treatments exhibited greater SBP reduction in women than men (-21.4 vs. -16.8 mmHg, p=0.009 in the ALC group; -21.9 vs -17.1 mmHg, p<0.001 in the A5 group). The sex-adjusted LSM difference in SBP reduction was 0.46 mmHg, with a 97.5%CI upper limit of 2.79 mmHg. The response rates (achieving SBP <140 mmHg and DBP <90 mmHg and/or reduction of SBP >=20 mmHg and/or DBP >=10 mmHg from baseline) were 73.1% for ALC and 75.3% for A5 groups (p=0.633). Adverse drug reactions (ADRs) occurred in 3 patients receiving ALC and 5 patients receiving A5, all being mild. Conclusions: The study demonstrated that the single-pill third-dose triple antihypertensive therapy is comparable to standard-dose monotherapy in reducing SBP over 8 weeks without increasing ADRs, providing further support for the low-dose combination antihypertensive drugs in the initial treatment of hypertension. (NCT05362110)

EARLY POST-OPERATIVE CLINICAL OUTCOMES IN PATIENTS UNDERGOING TOTAL KNEE ARTHROPLASTY COMPARING IN-PERSON CLINIC VERSUS TELEHEALTH-DELIVERED REHABILITATION PROGRAM: A NON-INFERIORITY TRIAL

INTRODUCTION AND AIMS Rehabilitation following total knee arthroplasty (TKA) is essential to mitigate delay in physical recovery and facilitate optimum patient outcomes. Telehealth is emerging as a cost-effective and efficacious delivery method. The aim of this study was to investigate the early post-operative outcomes of patients following a telehealth-delivered rehabilitation program (Tele) compared with those following conventional outpatient rehabilitation (Clinic) in patients following TKA. METHODS A single-blinded, randomized controlled non-inferiority trial was conducted, with 108 participants scheduled for primary TKA randomly allocated to a 6-week, telehealth-delivered rehabilitation program (n=54) or a 6-week supervised, in-person rehabilitation program (n=54). Knee flexion range of motion (KF-ROM) and the Quality of Life subscale of the Knee Injury and Osteoarthritis Outcome Score (KOOS-QOL) were collected pre-surgery and 7-weeks post-surgery. A linear mixed-effect model was used to assess differences between groups over time for both outcome measures. Change in KOOS-QOL of greater than 10 points was used to establish minimally clinically important change (MCIC), with chi square analyses used to assess between-group differences. RESULTS Baseline KF-ROM measures were 124.1° and 122.2° for telehealth-delivered and in-person groups respectively; and 108.7° and 111.6° at 7-week post-surgery. KOOS-QOL scores were 32.7 and 33.3 at baseline for the respective groups; and 60.9 and 62.9 at week-7. There were no significant differences in between group changes over time for both KF-ROM (mean difference = -2.9°, 95% CI = -7.7 to 1.8; p=0.226) and KOOS-QOL (mean difference = -2.1, 95% CI: -10.0 to 5.9; p=0.611). Chi square analyses revealed no differences between groups meeting the MCIC (Tele = 71%; Clinic = 79%) in KF-ROM (X2 = 0.78, p = 0.377). CONCLUSION Short term outcomes following TKA are not different between telehealth-delivered and conventional supervised rehabilitation. Telehealth may provide an effective rehabilitation option for patients undergoing TKA.

Comparison of interventional treatment options for coronary calcified nodules: A sub-analysis of the ROTA.shock trial

BackgroundThe optimal treatment for coronary calcified nodules (CNs) is still unclear. The aim of this study was to compare the modification of these lesions by coronary intravascular lithotripsy (IVL) and rotational atherectomy (RA) using optical coherence tomography (OCT). MethodsROTA.shock was a 1:1 randomized, prospective, double-arm multi-center non-inferiority trial that compared the use of IVL and RA with percutaneous coronary intervention (PCI) in severely calcified lesions. In 19 of the patients out of this study CNs were detected by OCT in the target lesion and were treated by either IVL or RA. ResultsThe mean angle of CNs was significantly larger in final OCT scans than before RA (92 ± 17° vs. 68 ± 7°; p = 0.01) and IVL (89 ± 18° vs. 60 ± 10°; p = 0.03). The CNs were thinner upon final scans than in initial native scans (RA: 17.8 ± 7.8 mm vs. 38.6 ± 13.1 mm; p = 0.02; IVL: 16.5 ± 9.0 mm vs. 37.2 ± 14.3 mm; p = 0.02). Nodule volume did not differ significantly between native and final OCT scans (RA: 0.66 ± 0.12 mm3 vs. 0.61 ± 0.33 mm3; p = 0.68; IVL: 0.64 ± 0.19 mm3 vs. 0.68 ± 0.22 mm3; p = 0.74). Final stent eccentricity was high with 0.62 ± 0.10 after RA and 0.61 ± 0.09 after IVL. ConclusionRA or IVL are unable to reduce the volume of the calcified plaque. CN modulation seems to be mainly induced by the stent implantation and not by RA or IVL.

Cost-effectiveness of pessary therapy versus surgery for symptomatic pelvic organ prolapse: an economic evaluation alongside a randomised non-inferiority controlled trial

ObjectiveTo evaluate the cost-effectiveness of pessary therapy as an initial treatment option compared with surgery for moderate to severe pelvic organ prolapse (POP) symptoms in secondary care from a healthcare...

PHYSICAL ACTIVITY AND MENTAL HEALTH IN AUSTRALIAN ADULTS WITH PSYCHOLOGICAL DISTRESS

INTRODUCTION & AIMS Adults with mental health concerns face compounded barriers to physical activity engagement. We recently conducted a randomised controlled trial to determine whether a lifestyle intervention targeting PA and nutrition was non-inferior to psychotherapy in managing depression (the CALM non-inferiority trial). While we demonstrated non-inferiority, participants assigned to the lifestyle intervention demonstrated improvements in dietary adherence and intake but not self-reported activity measures. The aim of this sub-study was to analyse actigraphy-derived measures to identify whether objective changes occurred and determine whether these were associated with mental health. METHODS This study included a sub-set of 36 of the 70 participants assigned to the lifestyle therapy intervention from the larger trial (ACTRN12621000387820) who were recruited based on indicative depression (Distress Questionnaire Scale 8+). A Fitbit Charge-2 measured daily steps (n), distance travelled (km), floors climbed (n) and minutes in sedentary, light, moderate and vigorous activity. Questionnaires measured psychological distress (Kessler-10), anxiety (Generalised Anxiety Disorder scale-7) and depressive symptoms (Patient Health Questionnaire-9). Linear mixed models determined within-group change over time. Spearman rank correlation coefficients examined associations between change scores over 8-weeks. RESULTS From baseline to 8-week follow-up, floors climbed increased 38% (mean change [95%CI]: 2.8 [0.0, 5.5], P=0.047) and minutes sedentary increased 9% (66.9 [20.8, 133.0], P=0.004). We found no change in daily steps, distance travelled, or minutes spent lightly, moderately, or vigorously active. Reducing sedentary time was associated with reduced depressive symptoms (rs=0.350, P=0.043), similarly increasing time spent in vigorous activity was associated with reduced psychological distress (rs=0.346, P=0.045). CONCLUSION Changes in activity were mixed, however vigorous physical activity and reduced sedentary time were associated with improved mental health in adults with psychological distress participating in a lifestyle therapy intervention for depression. Future investigations should seek to quantify minimum changes required to benefit mental health in this vulnerable population.

MP20-19 Bipolar Enucleation of the Prostate (BipolEP) versus Transurethral Resection of the Prostate: A Prospective Randomized Controlled Non-Inferiority Trial

MP20-19 Bipolar Enucleation of the Prostate (BipolEP) versus Transurethral Resection of the Prostate: A Prospective Randomized Controlled Non-Inferiority Trial

Comparison of Helicobacter pylori eradication rates between 7 and 14 days of tailored therapy according to clarithromycin resistance test: A randomized, multicenter, non-inferiority study.

Recently, a simple tailored therapy based on clarithromycin resistance has been implemented as Helicobacter pylori (H. pylori) eradication therapy. Nonetheless, despite the tailored therapy and frequent adverse events, studies on treatment period are lacking. This study aimed to compare the H. pylori eradication rates of 7-day and 14-day tailored therapy regimens according to clarithromycin resistance. This multicenter, prospective, randomized, noninferiority trial enrolled H. pylori-positive patients who were randomly assigned to 7-day and 14-day regimen groups, depending on the presence or absence of clarithromycin resistance by 23S rRNA gene point mutations. Standard triple therapy (STT) (20 mg rabeprazole, 1 g amoxicillin, and 500 mg clarithromycin twice daily) or bismuth quadruple therapy (BQT) (20 mg rabeprazole twice daily, 500 mg metronidazole thrice daily, 120 mg bismuth four times daily, and 500 mg tetracycline four times daily) was assigned by clarithromycin resistance. Eradication rates and adverse events were evaluated. A total of 314 and 278 patients were included in the intention-to-treat (ITT) and per-protocol (PP) analyses, respectively; however, 31 patients were lost to follow-up, whereas five patients violated the protocol. Both the 7-day and 14-day regimens showed similar eradication rates in the ITT (7-day vs. 14-day: 78.3% vs. 78.3%, p > 0.99) and PP (87.9% vs. 89.1%, p = 0.851) analyses. Non-inferiority was confirmed (p < 0.025). A subgroup analysis according to clarithromycin resistance (clarithromycin resistance rate: 28.7%) revealed no significant difference in eradication rates between the 7-day and 14-day STT (90.0% vs. 90.1%, p > 0.99) and BQT (82.5% vs. 86.5%, p = 0.757). Furthermore, adverse events did not significantly differ between the two groups. The 7-day triple and quadruple therapy according to clarithromycin resistance showed similar eradication rates, as compared to the 14-day therapy.

Adherence and acceptability of multiple micronutrient supplementation during pregnancy: Study protocol for a cluster-randomized non-inferiority trial in Cambodia

BackgroundIron and folic acid (IFA) supplements are currently provided to Cambodian women during pregnancy. However, recent research has found benefits of a multiple micronutrient supplement (MMS) over just IFA alone on several outcomes of perinatal and infant health. The Ministry of Health in Cambodia has proposed a transition from IFA to MMS but to effectively guide this transition requires implementation research on the acceptability and adherence to MMS (over IFA).MethodsThis non-inferiority trial aims to assess the adherence and acceptability of IFA (60 mg elemental iron and 400 μg folic acid) compared to MMS (standard UNIMMAP formulation including 15 micronutrients) during antenatal care in Cambodia. A prospective cohort of 1545 pregnant women will be assigned to one of three trial arms: (1) IFA for 90 days [IFA-90]; (2) MMS for 180 days with two distributions of 90-count tablet bottles [MMS-90]; or (3) MMS for 180 days with one 180-count tablet bottle [MMS-180]. Each arm will enroll 515 women across 48 health centers (clusters) in Kampong Thom Province in Cambodia. The primary outcome is the non-inferiority of adherence rates of MMS-180 compared to IFA-90, as assessed by tablet counts. Mixed-effects logistic and linear regression models will be used to estimate the difference in the adherence rate between the two groups, with an ‘a priori’ determined non-inferiority margin of 15%. Acceptability of MMS and IFA will be measured using a quantitative survey conducted with enrolled pregnant women at 30-day, 90-day, and 180-day time-points. DiscussionFindings from this study will guide an effective and feasible MMS scale-up strategy for Cambodia. Additionally, the findings will be shared globally with other stakeholders planning to scale up MMS in other countries.Trial registrationNCT05867836 (ClinicalTrials.gov, registered May 18, 2023).

Laser and Pelvic Floor Muscle Training for Urinary Incontinence: A Randomized Clinical Trial.

Pelvic floor muscle training (PFMT) is considered the first option as a conservative treatment for female stress urinary incontinence (SUI). However, there is still debate whether energy-based devices are effective for treating SUI. The objective of this study was to assess whether PFMT and fractional CO2 laser therapy may improve symptoms in women with SUI. A parallel, randomized, nonblinded, noninferiority trial included 94 of 144 women 18 years or older with SUI randomized into 2 groups. The CO2 laser group (n = 47) received 3 vaginal applications at monthly intervals. The PFMT group (n = 47) underwent 2 weekly sessions. Primary outcome was the mean difference of International Consultation on Incontinence Questionnaire-Urinary Incontinence Short-Form (ICIQ-UI-SF) total scores between groups after 3 and 6 months. Main secondary outcomes were questionnaires for assessment of pelvic floor symptoms (Pelvic Floor Impact Questionnaire-Short Form 7 [PFIQ-7]), sexual function (Female Sexual Function Index [FSFI]), and improvement after treatment (Patient Global Impression of Improvement [PGI-I]). A reduction in the ICIQ-UI-SF total score, PFIQ total score, and the Urinary Impact Questionnaire score was perceived between baseline and 3-6 months in both groups. CO2 laser did not reach the noninferiority margin when compared with PFMT in both follow-up periods and analyses. Pelvic floor muscle training has improved the FSFI desire domain between baseline and 3-6 months, whereas CO2 laser improved the FSFI orgasm, pain, and total score after 3 months and FSFI orgasm and total score after 6 months. PGI-I assessment has shown an improvement in both groups. Fractional CO2 laser therapy was noninferior to PFMT after 3-6 months of treatment. Both groups presented a reduction in the ICIQ-UI-SF scores, and both methods could be considered for women with SUI.

Unraveling variations and enhancing prediction of successful sphincter-preserving resection for low rectal cancer: A post hoc analysis of the multicenter LASRE randomized clinical trial.

Accurate prediction of successful sphincter-preserving resection (SSPR) for low rectal cancer enables peer institutions to scrutinize their own performance and potentially avoid unnecessary permanent colostomy. The aim of this study is to evaluate the variation in SSPR and present the first artificial intelligence (AI) models to predict SSPR in low rectal cancer patients. This was a retrospective post hoc analysis of a multicenter, noninferiority randomized clinical trial (LASRE, NCT XXXXXX) conducted in 22 tertiary hospitals across China. A total of 604 patients who underwent neoadjuvant chemoradiotherapy (CRT) followed by radical resection of low rectal cancer were included as the study cohort, which was then split into a training set (67%) and a testing set (33%). The primary end point of this post hoc analysis was SSPR, which was defined as meeting all the following criteria: (1) sphincter-preserving resection; (2) complete or nearly complete TME, (3) a clear CRM (distance between margin and tumor of 1mm or more), and (4) a clear DRM (distance between margin and tumor of 1mm or more). Seven AI algorithms, namely, support vector machine (SVM), logistic regression (LR), extreme gradient boosting (XGB), light gradient boosting (LGB), decision tree classifier (DTC), random forest (RF) classifier, and multilayer perceptron (MLP), were employed to construct predictive models for SSPR. Evaluation of accuracy in the independent testing set included measures of discrimination, calibration, and clinical applicability. The SSPR rate for the entire cohort was 71.9% (434/604 patients). Significant variation in the rate of SSPR, ranging from 37.7% to 94.4%, was observed among the hospitals. The optimal set of selected features included tumor distance from the anal verge before and after CRT, the occurrence of clinical T downstaging, post-CRT weight and clinical N stage measured by magnetic resonance imaging. The 7 different AI algorithms were developed and applied to the independent testing set. The LR, LGB, MLP and XGB models showed excellent discrimination with AUROC values of 0.825, 0.819, 0.819 and 0.805, respectively. The DTC, RF and SVM models had acceptable discrimination with AUROC values of 0.797, 0.766 and 0.744, respectively. LR and LGB showed the best discrimination, and all 7 AI models had superior overall net benefits within the range of 0.3-0.8 threshold probabilities. Finally, we developed an online calculator based on the LGB model to facilitate clinical use. The rate of SSPR exhibits substantial variation, and the application of AI models has demonstrated the ability to predict SSPR for low rectal cancers with commendable accuracy.

A comparative study between single injection (corner pocket approach) and double injection costoclavicular block: A randomized parallel arm, non-inferiority trial

BackgroundPrevious studies have shown that ultrasound guided costoclavicular block may require a double shot to provide adequate, rapid sensory and motor blockade. In this trial, we hypothesized that if the corner pocket approach (between axillary artery and median cord) is used instead of the central approach (at the midpoint of the 3 cords) when performing single-shot costoclavicular block, the onset of blockade would be non-inferior to the double-shot technique. MethodNinety patients undergoing upper limb surgery were randomized to 2 groups for ultrasound-guided costoclavicular block (CCB) at a tertiary hospital. One group received ultrasound guided single-shot CCB using the corner pocket approach and other received ultrasound guided double-shot – the first shot at the centre of the 3 cords and the second between the axillary artery and the median cord. An observer blinded to group assignment recorded blockade onset time (defined as the time required to achieve a minimal sensorimotor composite score of 14 out of 16 points). ResultsOf the 101 patients assessed for eligibility, 90 were recruited over period of 1 year (February 2022 to January 2023), with 45 in each group. Onset time was 22.1 ± 3.1 min in the single-shot group and 22.4 ± 2.9 min in the double-shot group. This difference was insignificant (P = .3). ConclusionTime to onset of blockade and full anaesthesia are similar in single-shot corner pocket CCB vs double-shot CCB. Further studies are required to determine the minimum effective volume of local anaesthetic required for the described technique.

Timing of fractional flow reserve-guided complete revascularization in patients with ST-segment elevation myocardial infarction with multivessel disease: Rationale and design of the OPTION-STEMI trial

Current guidelines recommend complete revascularization (CR) in hemodynamically stable patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD). With regard to the timing of percutaneous coronary intervention (PCI) for non-infarct-related artery (non-IRA), recent randomized clinical trials have revealed that immediate CR was non-inferior to staged CR. However, the optimal timing of CR remains uncertain. The OPTION-STEMI trial compared immediate CR and in-hospital staged CR guided by fractional flow reserve (FFR) for intermediate stenosis of the non-IRA. The OPTION-STEMI is a multicenter, investigator-initiated, prospective, open-label, non-inferiority randomized clinical trial. The study included patients with at least 1 non-IRA lesion with ≥50% stenosis by visual estimation. Patients fulfilling the inclusion criteria were randomized into 2 groups at a 1:1 ratio: immediate CR (i.e., PCI for the non-IRA performed during primary angioplasty) or in-hospital staged CR. In the in-hospital staged CR group, PCI for non-IRA lesions was performed on another day during the index hospitalization. Non-IRA lesions with 50%-69% stenosis by visual estimation were evaluated by FFR, whereas those with ≥70% stenosis was revascularized without FFR. The primary endpoint was the composite of all-cause death, non-fatal myocardial infarction, and all unplanned revascularization at 1 year after randomization. Enrolment began in December 2019 and was completed in January 2024. The follow-up for the primary endpoint will be completed in January 2025, and primary results will be available in the middle of 2025. The OPTION-STEMI is a multicenter, non-inferiority, randomized trial that evaluated the timing of in-hospital CR with the aid of FFR in patients with STEMI and MVD. URL: https://www. gov. Unique identifier: NCT04626882; and URL: https://cris.nih.go.kr. Unique identifier: KCT0004457.

Non-inferiority randomized controlled trial comparing CricOid pressure and para-laryngeal pressure in parturients undergoing cesarean delivery: NiCOP trial

BackgroundCricoid pressure has been surrounded with controversies regarding its effectiveness. Application of ultrasound-guided para-laryngeal (PL) force has been shown to occlude the esophagus effectively compared with cricoid pressure (CP) in awake patients. We hypothesized that there would be no meaningful difference in the change in antero-posterior esophageal diameter from with application of cricoid or para-laryngeal pressure in parturients undergoing cesarean delivery under general anesthesia. MethodsIn this prospective, randomized, non-inferiority trial, 40 parturients scheduled for elective cesarean delivery under general anesthesia were randomized to receive rapid sequence induction with either cricoid pressure (n = 20) or para-laryngeal pressure (n = 20). The antero-posterior diameter of the esophagus, measured by sonography, was the primary outcome. Visualization of the esophagus, its position in relation to the glottic aperture, esophageal occlusion, percentage of glottic opening (POGO), time to intubation, first pass success rate, overall success rate and adverse events like desaturation or bronchospasm were secondary outcomes. ResultsThe mean change in anterior-posterior diameter in the CP group was 0.17 ±0.1 cm vs. 0.28 ±0.1 cm in the PL group. The mean difference (CP-para-laryngeal pressure) between the groups was -0.11 (95% CI −0.17 to −0.1) cm. As the upper limit of the 95% CI was lower than the prespecified non-inferiority margin (δ = −0.2), non-inferiority was established (P <0.001]. There was no significant difference in the POGO score (P = 0.818), time to intubation (P =0.55), or intubation attempts (P = 0.99). ConclusionsPara-laryngeal pressure was non-inferior to CP in occluding the esophagus in parturients undergoing cesarean delivery under general anesthesia and furthermore, no significant deterioration in intubation parameters was seen.

Comparative efficacy of family mediated intervention versus early intensive behavioural intervention on symptom domains in children with autism spectrum disorder: A randomized controlled trial

BackgroundFamily Mediated Intervention (FMI) and Early Intensive Behavioural Intervention (EIBI) are found to be standard of care for children with Autism Spectrum Disorder (ASD). Comparison of their efficacy were assessed using ISAA as primary outcome measure. MethodsThis study was a parallel arm, open label, randomized active- controlled non-inferiority clinical trial. 50 Children diagnosed with ASD were randomized into FMI and EIBI groups. Clinical status was checked by using Indian scale for assessment of autism (ISAA), Oro- motor and sensory profile at baseline, after three and six months. ResultsDifference between change in mean ISAA score between FMI and EIBI group at the end of 6 months as per protocol (PP) analysis was −7.23 (CI=-18.41, 3.94), which was within pre-defined clinically relevant non-inferiority (NI) margin of – 24. FMI was found to be non-inferior to EIBI at the end of 6 months as the lower bound of 95% CI (-18.41) for ISAA score was higher than NI margin. ISAA scores were found to be statistically lower in both FMI and EIBI groups at the end point compared to baseline which indicated improvement in symptom severity. ConclusionFMI was non-inferior to EIBI as therapy for children with ASD at the end of six months. Finding also indicated longer duration of treatment is required for FMI to be superior. FMI can be recommended for children with ASD in view of improved ISAA scores reported in our study. Clinical trial registration numberCTRI/2020/08/027099 (Registered with Clinical Trials Registry- India)

D3/Penta 21 clinical trial design: A randomised non-inferiority trial with nested drug licensing substudy to assess dolutegravir and lamivudine fixed dose formulations for the maintenance of virological suppression in children with HIV-1 infection, aged 2 to 15 years

BackgroundThere is increasing interest in utilising two-drug regimens for HIV treatment with the goal of reducing toxicity and improve acceptability. The D3 trial evaluates the efficacy and safety of DTG/3TC in children and adolescents and includes a nested pharmacokinetics(PK) substudy for paediatric drug licensing. MethodsD3 is an ongoing open-label, phase III, 96-week non-inferiority randomised controlled trial(RCT) conducted in South Africa, Spain, Thailand, Uganda and the United Kingdom. D3 has enrolled 386 children aged 2- < 15 years, virologically suppressed for ≥6 months, with no prior treatment failure. Participants were randomised 1:1 to receive DTG/3TC or DTG plus two nucleoside reverse transcriptase inhibitors(NRTIs), stratified by region, age (2- < 6, 6- < 12, 12- < 15 years) and DTG use at enrolment (participants permitted to start DTG at enrolment). The primary outcome is confirmed HIV-1 RNA viral rebound ≥50 copies/mL by 96-weeks. The trial employs the Smooth Away From Expected(SAFE) non-inferiority frontier, which specifies the non-inferiority margin and significance level based on the observed event risk in the control arm. The nested PK substudy evaluates WHO weight-band-aligned dosing in the DTG/3TC arm. DiscussionD3 is the first comparative trial evaluating DTG/3TC in children and adolescents. Implications of integrating a PK substudy and supplying data for prompt regulatory submission, were carefully considered to ensure the integrity of the ongoing trial. The trial uses an innovative non-inferiority frontier for the primary analysis to allow for a lower-than-expected confirmed viral rebound risk in the control arm, while ensuring interpretability of results and maintaining the planned sample size in an already funded trial. Trial registrationInternational Standard Randomised Clinical Trial Number Register: ISRCTN17157458.European Clinical Trials Database: 2020–001426-57.ClinicalTrials.gov: NCT04337450